The purpose of this proposal is to establish a new Alzheimer's Disease Research Center (ADRC) at the University of California, San Francisco (UCSF). The UCSF ADRC proposes to integrate basic science and clinical resources to investigate the clinical, molecular, neuropathological and neuroimaging features of Alzheimer's disease (AD), non-AD dementias, and mild-cognitive impairment (MCI). The proposed ADRC has two overarching aims: 1) to bridge the gap between laboratory and clinical studies in dementia and aging and 2) to explore the early, heterogeneous and overlapping presentations of different neurodegenerative disorders. The new ADRC will help integrate the strong UCSF basic science and clinical neurology programs in an effort to promote new discoveries. To address these aims, the ADRC will be organized around five Cores and three Projects. The Administrative, Education and Outreach Core will provide support overall management, training, and minority outreach. The Clinical Core will maintain well characterized cohorts of patients with AD, frontotemporal lobar degeneration, progressive supranuclear palsy, corticobasal degeneration, Creutzfeldt-Jakob disease, and MCI. Atypical presentations of AD and MCI will be studied, with special interest in patients with isolated language or executive symptoms. The Data Management and Biostatistical Core will assure standardized collection, validation, and novel statistical analysis of data. The Neuropathology Core will obtain autopsy material from the ADRC cohorts and facilitate clinicopathological studies. The Neuroimaging Core will use 4 Tesla MRI to investigate differential diagnosis of dementia. One Project will develop novel reagents to study PrPC structure and evaluate the ability of proteins to detect PrPsc in mice. A second Project will evaluate the relationship between cognitive deficits and calcium-dependent proteins in mice and humans. The final Project will use data from a unique cohort of 1061 MCI cases from the State of California's Alzheimer's Disease Centers to identify outcomes, risk factors, and MCI subtypes. This Project will also evaluate amnestic and nonamnestic (language, executive and mixed) MCI patients in an effort to better define the heterogeneity of MCI. The new ADRC will, therefore, build upon existing strengths at UCSF to promote unique studies of AD and non-AD dementias and MCI that will have an impact both locally and nationally.